Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation

Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx

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Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation George S. Metsios a, b, c, *, George D. Kitas b, d a

Faculty of Education, Health and Wellbeing, University of Wolverhampton, UK Department of Rheumatology, Russells Hall Hospital, Dudley Group NHS Foundation Trust, Dudley, UK School of Physical Education and Sport Science, University of Thessaly, Greece d School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, UK b c

a b s t r a c t Keywords: Exercise Physical activity Rheumatoid arthritis Autoimmune disease Cardiovascular disease Inflammation Rehabilitation

Rheumatoid arthritis (RA) is characterised by functional disability, pain, fatigue and body composition alterations that can further impact on the physical dysfunction seen in RA. RA is also associated with systemic manifestations, most notably an increased risk for cardiovascular disease. There is strong evidence to suggest that increasing physical activity and/or exercise can simultaneously improve symptoms and reduce the impact of systemic manifestations in RA. However, implementation of interventions to facilitate increased physical activity and/or exercise within routine clinical practice is slow because of not only patient-specific and healthcare professional-related barriers but also lack of relevant infrastructure and provision. We review the evidence supporting the physiological adaptations and beneficial effects occurring as a result of increased physical activity and/or exercise in RA and propose an implementation model for facilitating the long-term engagement of patients with RA. We propose that implementation should be led, in a pragmatic manner, by rheumatology healthcare practitioners and supported by social innovation. © 2019 Elsevier Ltd. All rights reserved.

* Corresponding author. Faculty of Education Health and Wellbeing, Walsall Campus, Gorway Road, WS13BD, Walsall, UK. E-mail address: [email protected] (G.S. Metsios). https://doi.org/10.1016/j.berh.2019.03.013 1521-6942/© 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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Introduction Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, typically presenting as symmetrical polyarthritis of proximal small and other synovial joints. It affects approximately 1% of the adult general population, and it is accompanied by symptoms e such as pain, stiffness, swelling and fatigue e that may have debilitating effects on the functional ability and quality of life of affected patients. In addition, RA is accompanied by systemic manifestations, most notably an increased risk for cardiovascular disease (CVD), as well as detrimental changes in body composition, hence favouring increased fat mass deposition and reduced muscle mass [a condition termed ‘rheumatoid cachexia’ [1]]. These, in turn, further deteriorate function and the ability to perform daily tasks [1]. Therefore, it is not surprising that almost a third of patients with RA become unemployed as a result of their condition [2] and have 10 times the work disability rate compared to the general population [3]. The introduction of early, intensive anti-inflammatory/immune-modulating treatments and strategies involving conventional synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs) and, more recently, newer small molecules has significantly improved the health outcomes of these patients but, thus far, without substantial changes to their employment ability and with a significant increase (approximately 300%) in the direct healthcare costs [3]. As such, identifying beneficial, sustainable and cost-effective interventions that may alleviate the burden of RA for the individual, healthcare services and society as a whole should be adopted and implemented as part of routine clinical practice. Increase in physical activity is an intervention that can improve both disease-related and systemic manifestations in RA, while at the same time reduce the overall cost associated with the disease. Physical activity is any bodily movement that increases energy expenditure above resting levels, such as walking and gardening. Exercise, on the other hand, is a mode of physical activity that is planned, structured and repetitive, such as swimming three times per week. Over the last two decades, good-quality evidence has accumulated, clearly demonstrating that increasing physical activity is a behaviour that can significantly improve many different disease-related (e.g. fatigue, functional disability and inflammation) and systemic outcomes (e.g. CVD risk and body composition), as well as impact beneficially on RA costs. Specifically, in terms of cost, increased physical activity in RA is associated with a reduced number of hospital admissions and days of hospitalisation [4]; this is also confirmed in patients with CVD, where increasing physical activity through cardiac rehabilitation, is both an effective and cost-effective intervention for reducing national healthcare costs [5]. For health outcomes in RA, we and others have shown in systematic reviews (two published by the Cochrane Collaboration) that increased physical activity results in significant improvements in functional ability, cardiorespiratory fitness and strength [6e8], cardiovascular health [9] and fatigue [10]. Moreover, randomised and controlled clinical trials consistently demonstrate significant reductions in radiological damage in small and large joints, as a result of increased levels of physical activity participation [11e14], as well as reduced CVD risk and beneficial body composition changes that can reverse rheumatoid cachexia [14e17]. It is important to note that, increasing physical activity or engaging in different types of exercise, even in high-intensity exercise, is safe in RA, with no studies reporting any adverse effects [18]; in contrast, a sedentary lifestyle in RA can further promote the increased risk for future development of CVD [19e21]. Despite this well-described cumulative evidence about its beneficial effects, methods to improve physical activity levels in patients with RA are not incorporated in routine clinical care. Consequently, patients RA remain physically inactive, with activity levels well below those recommended [22], while their cardiorespiratory fitness e a factor that demonstrates very strong associations with all-cause and cardiovascular mortality [23] e is still alarmingly low [24]. Physiological effects of physical activity on RA symptoms and systemic manifestations Physical activity is a stimulus that results in significant functional and structural adaptations in different physiological systems, which, in turn, may beneficially impact on the overall RA symptomatology. The benefit of increasing physical activity and exercise is that it can simultaneously improve different physiological mechanisms, which with regard to RA, can benefit two main categories of outcomes for RA patients: disease-related symptoms and systemic manifestations. Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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Mechanisms mediating the beneficial effects of physical activity on RA symptoms Inflammation An area that has received significant research attention in the last few years is the antiinflammatory effects of physical activity. Exercise, a part of physical activity, is now considered a major stimulus that can result in anti-inflammatory effects. Exercise can induce both acute and longterm beneficial reductions in the inflammatory response in a dose-dependent manner (i.e. higher exercise intensities will result in more pronounced beneficial effects) through potentially different physiological mechanisms. The acute phase response depends on a vicious cycle that is based on the co-existence and crosstalk of pro-inflammatory cytokines, predominantly interleukins 1 and 6 (IL-1 and IL-6) and tumour necrosis factor alpha (TNFa). The kinetics of these inflammatory mediators, which are highly expressed in autoimmune diseases including RA, are different during exercise vs. sepsis/inflammation. Specifically, exercise-induced increases in IL-6 do not seem to promote an inflammatory state; instead, exerciseinduced increases in IL-6 mRNA expression are thought to act as a trigger for increasing hepatic glucogenolysis and lipolysis to provide more energy for the exercising muscles [25]. IL-1 and TNFa remain suppressed during a bout of exercise, whereas, they are highly overexpressed in sepsis and/or inflammation [25]. In support of this, macrophage (inflammation-induced) and intramuscular (exercise-induced) induction of IL-6 depends on different signalling pathways. Inflammation, which is based on IL-6 macrophage signalling, depends on the upstream and downstream signalling of IL-6, induced by the activation of nuclear factor-kB (NF-kB), and necessitates the presence of TNFa [26]. In contrast, exercise-induced overexpression of IL-6 occurs without an a priori overexpression of TNFa or NF-kB activation and is regulated by an interaction between the nuclear factor of activated T-cells and glycogen-p38 mitogen-activated protein kinase pathways [27]. At the same time, exercise-induced increases in IL-6 coincide with increases in the anti-inflammatory cytokines IL-10, soluble TNF receptor and IL-1 receptor antagonist [25]. Thus, an acute bout of exercise can induce an antiinflammatory phenotype. In the longer term, the anti-inflammatory effects of exercise are mainly based on its beneficial effects on body composition. Overweight and obese individuals demonstrate higher inflammatory load than the healthy population, while it has been observed that inflammatory processes are activated early in adiposity expansion and progression [28]. Indeed, obesity is now considered an inflammatory condition. The most recent systematic review and meta-analysis on the effects of exercise vs. hypocaloric diets on adiposity revealed that exercise can result in a greater loss of visceral fat in the absence of weight loss [29]. Reducing the size of adipocytes as a result of exercise results in lower levels of inflammation, even in populations with non-communicable, low-grade inflammatory diseases such as diabetes [30]. It is therefore thought that the long-term anti-inflammatory effects of exercise are mainly due to reduction of the size of adipocytes. Functional ability and fatigue There is growing evidence that physical activity and/or exercise can significantly improve disease activity and severity in patients with RA, hence facilitating significant improvements in their functional ability and quality of life. Perhaps the most comprehensive randomised controlled trial, the “rheumatoid arthritis patients in training” study, revealed that a two-year high-intensity exercise program of combined aerobic and strength training significantly improved functional ability of the exercising patients with RA vs. non exercising RA controls; at the same time, high-intensity exercise did not increase radiological damage in the large joints [11]. These results are in line with those of other, smaller randomised controlled trials in this field [31]. A 2009 systematic review and meta-analysis of eight studies in the Cochrane Library, which unfortunately has not been updated since, revealed that fitness and strength are significantly improved as a result of exercise training in patients with RA, a fact that may explain the significant benefits the patients experience in their functional ability [6]. The same review suggests that exercise may also reduce pain in RA. A more recent 2012 umbrella review of systematic reviews and meta-analyses (both Cochrane and non-Cochrane) revealed that the effect estimates for the efficacy of exercise therapy are generally smaller in RA than in other musculoskeletal conditions (i.e. osteoarthritis, low back and shoulder pain and fibromyalgia) for improving pain and Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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functional ability [32]. Moreover, despite that patients with RA may be at increased risk for falling, a 2010 Cochrane Collaboration systematic review concluded that no studies exist in the literature that address physical activity in relation to this particular outcome in RA [33]. Finally, a 2010 meta-analysis of randomised controlled trials (10 studies with 547 participants) concluded that resistance exercise training can improve different strength outcomes (isokinetic, isometric and grip strength) [8], which may have a potentially beneficial impact on functional ability and, as a result, performance in daily tasks. However, the quality of the studies included in this meta-analysis was evaluated using earlier research quality tools, and thus, the interpretation of these findings should be treated with caution. It seems apparent from the above that a) the existing meta-analyses need to be updated, as more recent trials have been published from 2010 to 2019 and b) more studies are required in this field to draw definitive conclusions. The effects of exercise programs on fatigue have also attracted attention in recent studies, as fatigue is a very commonly reported and debilitating symptom of RA. The most recent meta-analysis of five randomised controlled trials reveals that exercising for 12 weeks vs. no exercise results in significant reductions in fatigue in patients with RA. This is an interesting finding, as fatigue is reported by patients with RA to be one of the main barriers for non-participation in exercise programs [34] and poses significant questions with regard to the best ways to ‘convince’ people with RA to participate and remain in an exercise programme and how to achieve large-scale implementation of such programmes. Mechanisms mediating the beneficial effects of physical activity on RA systemic manifestations Cardiovascular disease Physical activity has been proposed as a key intervention for reducing the most predominant risk factors for developing CVD, namely, insulin resistance, hypertension and hypercholesterolaemia. Recent studies confirm that these beneficial effects are also evident in RA. The updated European League Against Rheumatism (EULAR) guidelines acknowledge these issues and have updated their guidelines to recommend lifestyle change for reducing the CVD burden in RA by including suggestions to increase physical activity [35]. For insulin resistance, exercise enhances the translocation of the insulin-mediated glucose transporter type 4 (insulin-regulated glucose transporter) to the sarcolemma, which may result in increased glucose uptake in the cell up to 24 h post-exercise [36]. This transient exercise-induced change in the translocation of insulin-mediated glucose transporter type 4 is thought to be the main mechanism that results in a long-term improvement in glucose homeostasis in individuals with an insulin-resistant phenotype. As such, it comes as no surprise that the most recent Cochrane Library meta-analysis reported that diabetics in exercise interventions (both aerobic and resistance training) had statistically and clinically significantly improved glycaemic control when compared to their non-exercising counterparts [37]. In RA, both higher physical activity and fitness (i.e. maximal oxygen uptake) levels have been associated with reduced insulin resistance [24,38], although the mechanisms have not been studied in detail in this population. The combination of increased physical activity and anti-TNFa therapy may hold great promise in improving insulin sensitivity, particularly in normal-weight RA, as anti-TNFa therapy seems to reduce insulin resistance [39]. Overall, insulin sensitivity is impaired with increasing body mass index in RA [40], a phenomenon that can be partly improved by engaging in physical activity. Elevated blood pressure is also a CVD risk factor that can be reduced by a clinically significant magnitude when physical activity is increased [41]. Immediately post-exercise, there is a reduction in blood pressure, which is thought to be caused by reduced peripheral vascular resistance [41,42]. In the longer term, exercise affects blood pressure through a variety of different mechanisms including enhanced baroreceptor sensitivity, reduced peripheral vascular resistance, improved endothelial function and vasodilator such as nitric oxide bioavailability and improved resistance to oxidative stress [42]. Findings specifically in patients with RA are well in line with these findings, although, again, the exact mechanisms have not been specifically studied in this population. Patients with RA with higher physical activity levels as well as higher maximal oxygen uptake have lower blood pressure than patients with RA with lower levels of physical activity or fitness [24,38]. Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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Various modes of exercise also have beneficial effects on lipoprotein profiles. Exercise-induced changes in lipid profiles are achieved in lecithin-cholesterol acyltransferase, which is an enzyme that converts cholesterol into cholesteryl ester, eventually facilitating the synthesis of the antiatherogenic high-density lipoprotein [43]. Furthermore, exercise induces increases in lipoprotein lipase [44], another enzyme with a major role in hydrolysing triglycerides into free fatty acids and glycerol. With regard to the effects of exercise on the major lipoproteins involved in atherosclerosis, a recent review of 15 studies (13 experimental studies and two reviews) confirms that exercise has beneficial effects on lipid profile in both healthy individuals and those with hypercholesterolaemia [45]. Participating in regular exercise can increase high-density lipoprotein and at the same time offset relevant increases in triglycerides and low-density lipoprotein in atherosclerosis [45]. Another metaanalysis of 49 randomised controlled trials in healthy men older than 18 years of age with elevated cholesterol demonstrated that aerobic exercise significantly improves total cholesterol, high-density lipoprotein and triglycerides, while for low-density lipoprotein, a beneficial non-significant trend was observed [46]. A separate meta-analysis by the same group of authors confirmed these beneficial exercise-induced effects on lipids in women [47], something that may be particularly relevant in RA. Studies on RA demonstrate that more physically active patients as well as those with higher levels of cardiorespiratory fitness have significantly better lipid profiles than those who have lower physical activity and fitness levels [24,38]; however, again, the exact mechanisms that may explain such associations in this population have not been studied per se. Several other exercise-induced effects may be of relevance in lowering CVD risk. The leading cause of CVD, atherosclerosis, can be beneficially managed by increasing physical activity and fitness levels. A key step in the evolution of atherosclerosis is the oxidation of low-density (LDL) lipoprotein in the endothelium. Increasing cardiorespiratory fitness levels, through appropriately designed exercise interventions, significantly reduces oxidised LDL [48]. Moreover, high-intensity exercise training does not enhance oxidative stress processes in patients with RA, while in the long term, 3-nitrotyrosine (a biomarker of nitrogen free radical species-modified proteins) significantly reduces, thereby supporting the findings seen in healthy populations that exercise counteracts the development of oxidative stressrelated mechanisms [49]. Finally, significant alterations occur in vascular function after exercise. Increasing shear stress due to exercise-induced haemodynamics results in functional and structural changes in the vasculature that help reverse CVD processes. Vascular function may be significantly impaired as a result of persistent inflammation in RA [50]. In contrast, exercise training for three or six months at intensities of up to 75% of maximum heart rate can significantly improve micro- and macrovascular function in RA, possibly through the effects of exercise to increase nitric oxide bioavailability, a key mediator for the maintenance of vascular homeostasis [13,51]. Rheumatoid cachexia Rheumatoid cachexia is a condition predominantly driven by the overexpression of TNFa [i.e. a similar pathway as that of cancer cachexia [52]] and characterised by increased resting metabolic demands [1,53]. This phenomenon can be further deteriorated by smoking [54]. This eventually results in significant alterations in body composition of patients with RA, characterised by increased fat deposition and reduced muscle mass compared to healthy age- and gender-matched adults [1]. Indeed, it has been suggested that the body mass index cut-off points for patients with RA should be altered for overweight and obesity to 23 kg/m2 (rather than 25 kg/m2) and 28 kg/m2 (rather than 30 kg/m2), respectively [55]. In the absence of established diagnostic criteria for rheumatoid cachexia, the prevalence of the syndrome ranges from 8% to 67% in the RA population [17]; however, it has been suggested that patients with RA who experience these detrimental body composition changes may have worse functional ability and disease symptoms as well as increased risk for CVD [1,56]. Blocking TNFa, through anti-TNFa medication, does not reverse rheumatoid cachexia up to a period of six months in patients with either early RA or established RA [57,58]. However, exercise is an intervention that can significantly reverse these phenomena by significantly increasing muscle mass with no adverse effects [15]. A summary of the mechanisms by which physical activity can improve disease-related and systemic manifestations in RA is shown in Fig. 1.

Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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Fig. 1. Overall mechanisms of the beneficial effects of physical activity and exercise on disease-related and systemic manifestations in RA.

Barriers for physical activity implementation in clinical practice Despite the well-documented benefits of physical activity and exercise on various different physiological mechanisms that can significantly ameliorate disease symptoms and improve the overall function and quality of life in RA [59], the physical activity and fitness levels of patients with RA remain significantly lower than those of the general population. The QUEST-RA study that investigated physical activity levels in patients with RA from 58 sites in 21 countries revealed that only 13.8% of patients with RA perform physical activity more than three times per week, i.e. the currently recommended levels [60]. Given the multiple different benefits of physical activity in RA, studies have focused on identifying the different barriers that may hinder participation. The most recent systematic review in this field reveals that patients with RA report as barriers factors that overlap with those observed in the general population, such as lack of time and cost [34]. However, the majority of studies identify also diseasespecific barriers particularly pain, fatigue and functional disability [34], all of which, interestingly and as already mentioned, can be significantly improved once patients start exercising [6,10]. The lack of physical activity and exercise in the RA population may also be due to other factors, predominantly influenced by rheumatology healthcare professionals. Until recently, the diagnosis of RA was accompanied by the advice to rest and avoid physical activity, as healthcare professionals feared that exercise may exacerbate disease symptoms and lead to further functional disability. Despite the overwhelming evidence that physical activity, even high-intensity exercise, is safe in RA and has no adverse effects, implementation of programmes aiming to enhance physical activity in routine clinical practice is still lacking. In line with this, patients with RA report as a main barrier for their reduced participation in physical activity the lack of advice and support from their managing rheumatology healthcare practitioners. This is confirmed by a recent review on barriers and facilitators for physical activity in RA as well as the most recent qualitative studies on physical activity engagement in RA [34,61,62]. How can we implement physical activity advice in clinical practice As described above, there is convincing data at present to suggest that increasing physical activity can improve disease outcomes in RA, thus leading to better disease management. It is expected, Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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therefore, that attempts would be made in the last decade to help implement programmes aiming to improve physical activity as integral parts of the overall management of RA, or at least that physical activity is promoted more actively within clinical practice. However, this is not the case. Several studies have addressed possible ways to help patients become and remain more physically active [63,64]. Irrespective of the outcomes of these studies, the long-term engagement in physical activity significantly suffers after the end of any intervention, as patients that previously engage with physical activity and/or exercise tend to become again physically inactive post intervention, which is a general phenomenon in other non-communicable diseases [65]. To address this important matter, we propose a theory for implementation that can effectively address key barriers from both (a) the healthcare practitioners' and (b) the patients’ perspectives to increase levels of physical activity; this is also based on the well- and long-known relationship between the managing rheumatology healthcare practitioner and the patient, a keystone in healthcare, which evidently promotes uptake and adherence to behaviours that can significantly improve health [66,67]. It is, however, important to note that this implementation model, although theory and evidence based, remains to be appropriately tested in relevant trials as a whole or in part. Addressing healthcare practitioners’ barriers for implementing physical activity in clinical practice At present, unfortunately, we and others have shown that there is a lack of provision from official bodies e such as the British Society of Rheumatology, EULAR, Arthritis Research UK and others e on physical activity advice for patients with RA, as well as advice to healthcare professionals and commissioners on how to effectively (a) incorporate physical activity in the clinical management of RA and (b) promote long-term adherence to a physically active lifestyle [68,69]. As such, even if individual attempts to promote and implement physical activity in clinical practice existed, the materials to support such initiatives (e.g. instruction on how to implement or how to address patient's aims in an individualised manner) are non-existent for RA. This is surprising, as embedding physical activity into healthcare streams and promoting long-term adherence are now recognised as priority targets by the World Health Organisation (WHO) for the effective management of non-communicable chronic diseases such as RA [70]. The WHO has proposed that physical activity implementation can be achieved with capacity building at the level of frontline healthcare practitioners managing the patients (i.e. in the case of RA, rheumatologist healthcare professionals) [71]. Unfortunately, a very low number of doctors involved in the management of RA (17%) have the confidence to prescribe physical activity for their patients [72], a fact revealing that relevant provision is probably necessary at all levels of a rheumatologist's professional career, from undergraduate, through postgraduate training, to specialisation and continuing professional development. In addition to that, information about physical activity, even when provided by the consulting doctors, is inconsistent at present, and there is uncertainty about how to advise patients with RA on increasing physical activity [73], which, as previously stated, is an important barrier for the patients [62]. For a wider implementation and scaling-up of physical activity engagement within the healthcare setup, we propose that this should be led by the main healthcare practitioners involved in the patient's management during routine clinical visits, in a repetitive, enabling and reinforcing fashion. Education about the mechanisms and benefits of physical activity on different health parameters is not covered extensively in the curricula of Medical Degree programs [74] and even less afterwards. Therefore, while “deep infrastructure” is developed at all levels/stages of a health practitioner's career, perhaps a viable interim solution to address this problem could be expert-led e-learning capacity-building initiatives. Elearning education is a preferable method of learning for healthcare practitioners, while collective evidence reveals that it can facilitate wider dissemination and scaling-up of successful practices [75]. Capacity building of frontline healthcare professionals for incorporating physical activity in clinical practice is also in line with recent recommendations from the WHO and other national authorities for optimising healthcare in a sustainable manner [70]. Considering the financial pressures on National Health Services, physical activity implementation should also be cost-effective; hence, potentially, the inclusion of brief but meaningful physical activity advice during routine patient visits (i.e. a pragmatic approach) may be an intervention that holds great promise [76], but this needs to be prospectively evaluated in RA. Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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The above suggestion is also supported by good-quality evidence. Strong evidence has emerged from other disease entities that when healthcare practitioners incorporate physical activity advice in their clinical practice, they can significantly contribute towards altering behaviours and help patients with other chronic non-communicable diseases to become more physically active. Specifically, when clinicians in primary care were trained to deliver brief (3e4 min) interventions during routine patient visits, this resulted in increased levels of physical activity over a 2-year follow-up as well as significant improvements in cardiorespiratory fitness [77]. In addition, the PREMIER and SMARTER trials [78,79] provided strong evidence that brief lifestyle and physical activity counselling among adults with prehypertension or stage 1 hypertension and/or diabetes [both highly prevalent in RA [80e82]] resulted in a significant reduction in cardiovascular risk with excellent sustainability. These results are also in line with those in research on RA. A randomised controlled trial investigating the effects of patient education about the benefits of improving lifestyle vs. standard care demonstrated that the intentions and behaviours of the patients with RA change beneficially, and importantly, this can significantly reduce blood pressure, while such changes were not observed in the control group [83]. Brief (3e4 min) healthcare practitioner-led advice on physical activity during routine patient visits (a) using specific guidelines and current national recommendations [76,84] and after (b) adequate expertdeveloped e-learning capacity building could therefore help overcome one of the most important barriers within clinical practice to address the lack of physical activity implementation in the clinical care of RA. Addressing patients’ barriers for a sustainable increase in physical activity Incorporating advice about physical activity and reinforcing its importance with viable targets during routine clinical visits, therefore, is the first key step. In line with this, several different lines of evidence reveal that physical activity as part of the management of RA is very rarely discussed in routine face-to-face rheumatologistepatient visits [72], and the time allocated for such a discussion remains inadequate. Therefore, it is not surprising that patients with RA still identify the lack of clarity and support for physical activity from their physicians/nurses as a main barrier to their participation [85]. In contrast, receiving such information has been shown e in early qualitative studies e to be associated with higher levels of physical activity engagement among patients with RA [86]. Moreover, a recent qualitative study revealed that patients require physical activity advice from their “trusted health professionals” to become more physically active but, most importantly, to adhere to such a lifestyle [61,62]. In addition to the above, empowerment for patients with RA from trusted healthcare professionals to develop their knowledge about the safety and effectiveness of physical activity is key, particularly to understand that their own main barriers e i.e. fear of exacerbating symptoms such as pain and fatigue and further worsening functional ability e can be significantly improved by exercising. Thus, if our first proposed step for the capacity building of healthcare professionals does not take place, the improvement in knowledge/education of the patients about the beneficial mechanisms of physical activity in RA may be inadequate, and the response effectiveness will lack specificity, thus, compromising longterm sustainability of the beneficial effects of physical activity. Importantly, another key factor to support a sustainable increase in physical activity in RA is through disruptive social innovation, i.e. the empowerment of the communities (patient organisations, community groups, third-sector exercise professionals) to support either (a) physical activity referrals from healthcare practitioners or even (b) implement physical activity interventions for patients with RA on their own. Capacity building of exercise professionals, patient volunteers and/or third-sector organisations through the development of relevant workshops and seminars to help them develop their knowledge of how to perform exercise in patients with RA is key for a sustainable implementation. For example, when exercise coaches and volunteers know how to develop individualised and safe exercise interventions for patients with RA, which are incentivised and formally rewarded, while, at the same time, offering a range of activities (e.g. dance, water-based activities, modified sports such as walking football, tai-chi etc.), is also an important factor for developing sustainable physical activity interventions. In the United States, a similar approach exists with the ‘exercise pharmacies’ for patients with CVD, whereby healthcare professionals confidently refer patients with CVD to exercise Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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professionals/community-build programs to improve their health outcomes [87]. In such a way, patients with RA can attend disease-specific physical activity RA referral schemes with a variation of physical activities, which may further contribute to long-term sustainability. It is important to note that this approach addresses established patient-identified barriers for reduced physical activity and specifically the lack of (a) RA-specific physical activity programs and (b) knowledgeable exercise instructors [34]. Physical activity advice in clinical practice and referral process A schematic representation of our healthcare practitioner-led implementation suggestion for the long-term sustainability of physical activity is given in Fig. 2. Step 1: Patients with early RA or those with longstanding RA are currently best treated with a treatto-target approach, based predominantly, if not exclusively, to semi-objective assessment of their disease activity. Irrespective of their current disease status, and alongside any decisions about the best possible pharmacological management, patients should be informed briefly during their routine visits that implementing appropriate lifestyle modifications, including becoming more physically active, is

Fig. 2. Healthcare practitioner-led model for the implementation of physical activity.

Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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also important and will be needed for effective long-term management. This first introduction of the role of physical activity should be consistently reinforced by all rheumatology health professionals in every subsequent visit. Once the inflammatory component of the disease is sufficiently controlled, patients should be motivated to engage in physical activity with specific targets agreed with them (e.g. increase steps/week, see Fig. 2). The first viable and easy way to achieve this is by increasing walking time, a mode that improves significantly health outcomes [88]. Current suggestions for public health suggest walking 10,000 steps/day, with 3000 steps/day equating to approximately 30 min of moderate physical activity [89]. As a first step to increase physical activity, this information can be briefly provided/prescribed within clinical practice by the managing rheumatologist and reinforced consistently by all members of the rheumatology multidisciplinary care team. Alternatively, based on their current physical activity levels (minutes or steps/week), physically inactive patients should be motivated to progressively reach the recommended levels of physical activity levels equating to 150 min/week (rather than steps/day, as per the previous example). Targets to reach the recommended physical activity should be based on current levels and be revisited and revised in every routine patient visit. Not achieving previously agreed targets should be briefly discussed, and healthcare professionals should try to further motivate patients to reach their targets by their next routine visit. However, it is important to note that the current established public health recommendations suggest 150 min/week of moderate to vigorous physical activity, combined with resistance training twice a week. Implementation of these recommendations is likely to exceed the knowledge, competence and even timeavailability of rheumatology healthcare professionals; hence, once step targets are reached, onwards referral to exercise physiologists could be considered. Step 2: Empowerment of patients with RA to understand that physical activity is key for their longterm management is also necessary. This advice can also be brief and should always be accompanied by ensuring patients that physical activity is (a) safe and (b) can improve the main RA symptoms that may currently inhibit their participation in physical activity (i.e. functional disability, pain and fatigue). In addition to the above approach, patient-centred approaches could also facilitate implementation. Such an initiative has been developed recently by the most prominent organisation for patients with RA in the UK, the National Rheumatoid Arthritis Society (NRAS). This is a freely available online interactive e-program developed by patients themselves, facilitated by experts, and aims to help patients with RA to set specific goals to self-manage risks related to their condition as well as mitigate their CVD risk (e.g. adherence to medication, increasing physical activity and improving diet). The program is firmly based on research work that has been progressively developed over many years by a collaboration of patients, rheumatology health professionals, exercise physiologists, behavioural scientists and educationalists aiming to implement lifestyle interventions to reduce CVD risk in people with RA [77]. However, its effectiveness and reach remain to be formally evaluated. Step 3: Capacity building of communities (e.g. exercise and sports coaches, patient volunteers and exercise instructors in local gyms) that can support physical activity is also necessary, albeit this is a public health rather a healthcare matter. Developing knowledge of how to perform exercise in people with RA and incentivising physical activity professionals (gym instructors, sports coaches and physical activity community groups) with relevant awards will help develop a body of professionals that will be able to help patients with RA exercise safely and progressively to achieve improvements in disease symptoms as well as overall health benefits. The purpose of these initiatives, which have to be reinforced by the managing healthcare practitioners during routine visits, has to be the aforementioned specific recommended targets of 150 min/week (moderate to vigorous intensity with the addition of resistance training) to optimise the healthcare management of patients with RA. A single, clear, simple and consistent message reinforced by all involved in the care pathway of a patient with RA (from community to primary and secondary care and beyond) is essential for future change. Summary Increasing physical activity and/or exercise can beneficially and simultaneously impact on different disease-related symptoms and systemic manifestations of RA. However, implementing physical activity in routine practice has always been a challenge for healthcare practitioners because of unfounded patientspecific barriers, lack of understanding or misconceptions of health practitioners and lack of relevant Please cite this article as: Metsios GS, Kitas GD, Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation, Best Practice & Research Clinical Rheumatology, https:// doi.org/10.1016/j.berh.2019.03.013

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infrastructure and provision. Implementation of physical activity in clinical practice can be led, in a pragmatic manner, by rheumatology healthcare practitioners during routine patient visits and supported by social innovation. The main constituents of an implementation model are proposed based on current evidence and expert opinion, but its effectiveness and cost-effectiveness should be tested in appropriately designed trials.

Practice points  Rheumatoid arthritis is characterised by symptoms and functional limitations that can interfere with regular engagement in physical activity. It is also associated with systemic manifestations, most notably cardiovascular disease.  The cost of rheumatoid arthritis is proportionately higher than that of other noncommunicable diseases.  Physical activity and exercise are safe and effective interventions to ameliorate symptoms and systemic manifestations of rheumatoid arthritis.  Implementation of physical activity interventions in clinical practice remains extremely limited; it should be led e in a pragmatic manner e by rheumatology healthcare practitioners and supported by social innovation.

Research agenda  More methodologically robust studies are required to understand the effects of physical activity on different physiological mechanisms in RA, including inflammatory, cardiac and inflammatory responses  Research is currently required to better understand how to implement physical activity in clinical practice, given the multiple beneficial effects of physical activity on RA clinically and patient-important outcomes

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